CN1084618C - 5－羟色胺拮抗剂的新应用 - Google Patents

5－羟色胺拮抗剂的新应用 Download PDF

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CN1084618C
CN1084618C CN95192946A CN95192946A CN1084618C CN 1084618 C CN1084618 C CN 1084618C CN 95192946 A CN95192946 A CN 95192946A CN 95192946 A CN95192946 A CN 95192946A CN 1084618 C CN1084618 C CN 1084618C
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cycloalkyl
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CN1147767A (zh
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W·米勒
T·施特拉茨
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Nova Altice Co Ltd
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Abstract

5-HT3拮抗剂可用于治疗纤维肌痛症。

Description

5-羟色胺拮抗剂的新应用
本发明涉及5HT3拮抗剂的新应用。
下面将介绍的化合物系本发明之化合物。
5HT3拮抗剂是一类阻断5HT3受体的化合物。其例包括比利时专利897117，900425和901274所述化合物。其中所述这些化合物称为5HT3受体拮抗剂，或5-羟色胺M受体拮抗剂(5-羟色胺M受体已再分类为5HT3受体)。
本发明化合物的其它类型，是例如欧洲专利公开号13138A，200444A和214772A，以及英国专利公开号2153821所公开过的化合物。
各种来源公开的5HT3拮抗剂有很广泛的不同用途，例如用于治疗内脏疼痛、偏头疼、血管及集结性头疼、三叉神经疼、心律不齐、5-羟色胺诱导的胃肠功能紊乱(包括抗癌剂引起的呕吐)、焦虑症与紧张相关的精神紊乱、抑郁症、识别紊乱症、社交孤僻症、恐慌发作、旷野恐怖症、肺栓塞、鼻炎或5-羟色胺诱导的鼻病，用于提高警觉性，或者用于治疗由诱导依赖性药物引起的药瘾症。有些治疗呕吐的该拮抗剂已引入市场。
目前出人意料地发现本发明化合物对患纤维肌痛症的患者有明显的改善作用，该病的主要症状包括疼痛以及功能性和植物神经性紊乱，且持续时间超过治疗时间。
纤维肌疼(也称为纤维织炎，或统称腱肌病)是很普遍的一种疾病，其特征是运动器官的各部位疼痛、僵硬，特别是对压力很敏感的腱插入和腱鞘部位，而且还出现功能性和植物神经性紊乱、以及出现抑郁症状、神经官能症等神经病理状况。
功能性症状的例子是睡眠失调，头疼、偏头疼、晕眩感觉、功能性呼吸和心脏不适、胃肠道紊乱和尿痛。植物神经性症状的例子是肢端发凉、多汗、嘴发干、皮层划痕现象、发抖、呼吸性心律失常，和直立困难。
纤维肌痛症的治疗是困难的且不能令人满意。该病尚无有效治疗法可用。曾试图使用止痛药和非类固醇抗炎药止痛均不成功。很高剂量的肌松剂也仅表现出有限的活性，而且，高剂量也诱导严重付作用，不得不停止使用。也曾建议使用阿米替林之类的抗抑郁药，它们对患者的某些亚群体表现出一些活性，但该活性会很快降低。
本发明化合物包括游离形式或可药用之盐或配合物形式的式I化合物，
其中
R1是氢，卤素，羟基，烷氧基(1-4C)，氨基，烷(1-4C)氨基或二烷基(1-4C)氨基；
R2是氢，烷基(1-7C)，链烯基(3-6C)，炔基(3-10C)，环烷基(3-7C)，环烷基(3-7C)烷基(1-4C)，苯基，苯烷基(1-3C)，烷基(1-6C)羰基，烷基(1-6C)氧羰基，氨基甲酰基，氨磺酰基，或单、双烷基(1-6C)氨基甲酰基或氨磺酰基；
X是CH或N，
Y是NR3或O，其中R3是氢或烷基(1-6C)，或
X+Y连在一起是C-A-N或C-A-CH，其中A是CH＝CH或-(CH)m-，m是2或3；
n是0、1或2；
Z是式(a)基团，其中：o是0，p是0、1或2，并且q是0、1或2；或
o是1，p是0，而q是0或1；且
R4是氢，烷基(1-7C)，环烷基(3-6C)，
由卤素、烷基(1-4C)或烷氧基(1-4C)任选单或
双取代的苯基烷基(1-4C)；或者Z是式(b)基团，
Figure C9519294600071
其中：o’是1、2或3，p’是0或1，而q’是0或1；或者Z是式(c)或(d)基团，
Figure C9519294600072
其中：R5、R6和R7之一是氢，烷基(1-6C)，环烷基(3-7C)，
      链烯基(2-6C)，苯基或苯烷基(1-3C)，而其余
      两个各自是氢或烷基(1-6C)，其前提条件是当n是0，
      而y是NR3或与X一起为N-A-C时，Z不能是(d)。
R1优选为氢或甲氧基。
R2优选为氢或烷基(1-7C)。
对于R2采说，烷基(1-7C)优选为烷基(1-4C)，更优选甲基；链烯基(3-6C)优选为链烯基(3-4C)；炔基(3-10C)优选为炔基(3-4C)；环烷基(3-7C)优选为环烷基(3-6C)；环烷基(3-7C)烷基(1-4C)优选为环烷基(3-6C)甲基；苯基烷基(1-3C)优选为苄基；烷基(1-6C)羰基优选为烷基(1-4C)羰基；烷基(1-6C)氧羰基优选为烷基(1-4C)氧羰基；而二烷基(1-6C)氨基甲酰基和氨基磺酰基优选为二甲基氨基甲酰基和二甲基氨基磺酰基。
R3优选为氢或甲基。
R4(式(a)中)优选氢或烷基(1-4C)，更优选甲基。
R5、R6和R7(式(c)和(d)中)之一优选甲基，其余二者优选氢。更为优选R5是甲基，而R6和R7是氢。当X+Y连一起是C-(CH2)m-CH时，m优选2。
式(a)中优选o是0，p和q是1，或p是1而q是0。
若Z是式(a)或(b)，则n优选0；若Z是式(c)或(d)，则n优选1。
式I化合物的一类中，R1是烷基(1-4C)、R2是氢、X是CH、Y是O或NH、n是0、而Z是式(a’)、
其中R4’是甲基、乙基或丙基，而q”是0、1或2。
由上面定义的取代基性质所决定，该分子中可以存在不对称碳原子。例如当X+Y连一起是C-A-CH的情况下便是如此。所有的旋光异构体和包括其外消旋混合物在内的旋光体混合物均是本发明之部份。
而且由Y-(CH2)n-Z基的性质所决定、该化合物可以有外型或内型构型。所谓外/内型命名法是文献中通用的。同样，外型和内型及其混合物均属本发明之部份。
其中优选内型。
式I化合物可以以游离形式或盐的形式存在。适宜的盐包括酸加成盐和季铵盐。
本发明化合物可以从下述化合物中挑选：
吲哚-3-基-甲酸-内-8-甲基-8-氮杂双环〔3，2，1〕-辛-3-基酯(其盐酸盐称之为托烷司琼，下面称化合物A)；
苯并〔b〕噻吩-3-基-甲酸-内-9-甲基-氮杂双环〔3，3，1〕壬-3-基酯；
5-氟-1-甲基-吲哚-3-基-甲酸-内-9-甲基-9-氮杂双环〔3，3，1〕壬-3-基酯；
1，2，3，9-四氢-9-甲基-3-〔(2-甲基-1H-咪唑-1-基)-甲基〕-4H-咔唑-4-酮(也称为昂丹司琼，下面称化合物B)；
1-甲基-吲唑-3-基-甲酸-9-甲基-9-氮杂双环-〔3，3，1〕壬-3 α-基-酰胺(也称之为格拉司琼)；
内-4-氨基-5-氯-2-甲氧基-N-(1-氮杂双环〔3，3，1〕壬-4-基)-苯甲酰胺；
3-〔5-甲基-1H-咪唑-4-基〕-1-(1-甲基-1H-吲哚-3-基)-1-丙酮；
N-(氮杂双环〔2，2，2〕辛-3-基)-6-氯-4-甲基-3-氧代-3，4-二氢-2H-1，4-苯并噁嗪-8-甲酰胺(也称之为azasetron)；
N-(内-8-甲基-8-氮杂双环〔3，2，1〕辛-3-基)-2，3-二氢-2-氧代-1H-苯并咪唑-1-甲酰胺；
7-甲氧基-1H-吲哚-3-甲酸-(1αH，5αH)-8-甲基-8-氮杂双环〔3，2，1〕辛-3α-基酯；称为GR87442的化合物。
进一步优选的5HT3拮抗剂包括：4，5，6，7-四氢-5-〔(1-甲基-吲哚-3-基)羰基〕苯并咪唑；(+)-10-甲基-7-(5-甲基-1H-咪唑-4-基-甲基)-6，7，8，9-四氢吡啶并〔1，2-a〕吲哚-6-酮；
N-(1-乙基-2-咪唑啉-2-基-甲基)-2-甲氧基-4-氨基-5-氯苯甲酰胺。
本发明在治疗纤维肌痛中的意想不到的效果由临床试验认定。
该临床试验中，根据W.Müller和J.Lautenschlger在Z.Rheumatol49：11-21(1991)中所述的方法，试验临床诊断为步行纤维肌痛症患者：使用10cm类似的视觉评分法，测患者自身额定值(即0＝无痛；10＝严重疼痛)，于身体各位点进行“疼痛评分”(疼痛严重程度)，并测定24个触疼点的数字测痛仪触痛评分值。一个触痛点是深触诊的剧痛面。此外，就有关功能性/植物神经性症状询问患者后填表，评定为明显(3)、中度(2)、轻微(1)或无症状(0)。这些症状包括：
手脚发凉
口干
多汗
头昏眼花
发抖
睡眠不安
胃失调
肠失调、便秘/腹泻
喉咙哽咽
周期性呼吸窘迫(非劳累所致)
心动过速/心律不齐
嗜睡、麻刺感及身体各部位其它不正常感觉
尿痛
头痛或偏头疼
感觉异常
根据Wilcoxon试验或Mann-Withney U-试验，该结果的统计学分析是有效的。
在一个此类试验中，给17个患者口服本发明化合物A5天，每日2×5mg。发现其中8个是极好应答者(≥40％得到改善，用视觉类似法评分)，其结果如下：
各测试方法均观察到明显改善：类似视觉评分法(P＝0.0142)，疼痛评分法(P＝0.014)，测痛仪法(平均压力触发疼痛P ＝ 0.0208，触疼点数P＝0.0346)，而植物神经性症状评估(P＝0.0109)。
在以化合物A进行的另一试验中；试验40个患者。第一组20人每日2×5mg共10天，第二组20人每日3×5mg共10天。发现18个患者(各组9个)是极佳应答者(用类似视觉评分法或疼痛评分法测定有≥40％得到改善)，其结果如下：
观察到的明显改善；类似视觉评分法(P＜0.0003分值从7.6降到2.6)，疼痛评分法(从55.8降至22.6)，测痛计法(平均压力触疼P＜0.06由1.91kp降到2.24kp；触痛点数P＝0.0346，由19.4降至14.2，)而植物神经性和功能性症状也得到明显改善。例如观察到的明显改善症状：睡眠不安(P＜0.006)、手脚发凉(P＜0.002)、头疼(P＜0.03)、感觉异常(P＜0.008)、心动过速/心律不齐(P＜0.006)以及周期性呼吸窘迫(P＜0.006)。
令人惊异地是在该试验中成功地改善疼痛和植物神经性症状可持续治疗后数周时间。
另一试验是以本发明化合物B进行，用20个患者作双育试验。这些病人口服该化合物2×8mg/天，共5天，停药2天后，口服扑热息痛2×500mg/天，共五天(或者随机地可将服药顺序颠倒)。7个患者是前面所定义的化合物B的极佳应答者，其结果如下：
观察到明显改善：类似视觉评分法(P＝0.003)、疼痛评分(P＝0.022)、测痛仪法(对于平均压力P＝0.008，而触痛点数P＝0.018)，而植物神经性症状评估(P＝0.003)。
采用扑热息痛的情况下，以类似视觉尺度法和疼痛评分法均未观察到明显改善。用测痛仪则明显为负值(压力触痛降低、P＝0.028；触疼点数增加，P＝0.029)。
再次证明，用化合物达到良好结果，可持续治疗后数周之久，在此期间，病人总的状况得到明显改善。
这些试验表明了该化合物的有效和缓解疾病(仅指对抗症状而言)活性。
因此本发明化合物能用于治疗纤维肌痛症。
当然对于该适应症适当的剂量取决于所采用的化合物、待治疗者、给药模式、所治疗症状的性质和严重程度。所显示的日剂量在通常已知的呕吐之类的适应症所用量范围内，一般约0.05-约50mg，按常规给药，例如每天分至多4次服用，以单位剂量形式，或以持续释放形式给药。
本发明化合物可按任何常规途径给药，特别是经肠道给药、优选以片剂或胶囊口服、或者经非肠道给药、例如注射溶液或悬浮液。
本发明也提供药物组合物，该组合物包括该治疗纤维肌痛症的化合物与至少一种药物载体或稀释剂相结合。此类组合物按常规方式制造。单位剂量形式例如可以含约0.01mg至约25mg该化合物。
本发明进一步提供本发明化合物在制造治疗纤维肌痛症之药物组合物中的应用。
本发明还提供对需要此种治疗的个体进行纤维肌痛症治疗的方法，该方法包括给所述个体施用治疗有效量的本发明化合物。

Claims (4)

1.5-HT3拮抗剂在生产治疗纤维肌痛症的药物组合物中的应用。
2.根据权利要求1的应用，其中5-HT3拮抗剂是游离形式或可药用的盐或配合物形式的式I化合物：
Figure C9519294600021
其中
R1是氢，卤素，羟基，烷氧基(1-4C)，氨基，烷(1-4C)氨基或二烷基(1-4C)氨基；
R2是氢，烷基(1-7C)，链烯基(3-6C)，炔基(3-10C)，环烷基(3-7C)，环烷基(3-7C)烷基(1-4C)，苯基，苯烷基(1-3C)，烷基(1-6C)羰基，烷基(1-6C)氧羰基，氨基甲酰基，氨磺酰基，或单、双烷基(1-6C)氨基甲酰基或氨磺酰基；
X是CH或N，
Y是NR3或O，其中R3是氢或烷基(1-6C)，或
X+Y连在一起是C-A-N或C-A-CH，其中A是CH＝CH或-(CH)m-，m是2或3；
n是0、1或2；且
Z是式(a)基团，其中：o是0，p是0、1或2，并且q是0、1或2；或者
  o是1，p是0，而q是0或1；且
  R4是氢，烷基(1-7C)，环烷基(3-6C)，由卤素、烷基
   (1-4C)或烷氧基(1-4C)任选单或双取代的苯基烷基
   (1-4C)；或者Z是式(b)基团，
Figure C9519294600032
其中：o’是1、2或3，p’是0或1，而q’是0或1；或者Z是式(c)或(d)基团，
Figure C9519294600033
其中：R5、R6和R7之一是氢，烷基(1-6C)，环烷基(3-7C)，
      链烯基(2-6C)，苯基或苯烷基(1-3C)，而其余
      两个各自是氢，或烷基(1-6C)，其前提条件是当n是0，
      而y是NR3或(与X一起)为N-A-C时，Z不能是(d)。
3.根据权利要求1的应用，其中5-HT3拮抗剂是游离形式或可药用之盐或配合物形式的吲哚-3-基-甲酸-内-8-甲基-8-氮杂双环[3，2，1]-辛-3-基酯。
4.根据权利要求1的应用，其中5-HT3拮抗剂是1，2，3，9-四氢-9-甲基-[(2-甲基-1H-咪唑-1-基)-甲基]-4H-咔唑-4-酮。
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